Long-term safety and tolerability of aripiprazole once-monthly in maintenance treatment of patients with schizophrenia W. Wolfgang Fleischhacker a , Raymond Sanchez b , Brian Johnson b , Na Jin c , Robert A. Forbes b , Robert McQuade b , Ross A. Baker b , William Carson b and John M. Kane d The aim of this study was to evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) for the maintenance treatment of schizophrenia. This long-term, pivotal study had four phases: oral conversion (phase 1, 4–6 weeks); oral stabilization (phase 2, 4–12 weeks); ARI-OM stabilization with coadministration of oral aripiprazole in the first 2 weeks (phase 3, 12–36 weeks); and a 52-week, randomized [phase 4, ARI-OM vs. placebo (2 : 1)], double-blind, maintenance phase. Safety was assessed across study phases by the time of first onset of adverse events, as were objective measures of extrapyramidal symptoms, fasting metabolic parameters, and body weight. Patient enrollment was phase 1 = 633; phase 2 = 710, of whom 210 entered phase 2 directly; phase 3 = 576; and phase 4 = 403 (ARI-OM, n = 269; placebo, n = 134). Adverse events (> 5%) in any phase were insomnia, headache, anxiety, akathisia, increase in weight, injection-site pain, and tremor. Headache, somnolence, and nausea had a peak first onset within 4 weeks of treatment initiation. The incidence of extrapyramidal symptoms was similar in all phases. There were no unexpected changes in weight or shifts in fasting metabolic parameters across all study phases. ARI-OM had a safety and tolerability profile comparable with oral aripiprazole in maintenance treatment of schizophrenia. Int Clin Psychopharmacol 28:171–176  c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. International Clinical Psychopharmacology 2013, 28:171–176 Keywords: aripiprazole, long-acting injection, safety, schizophrenia, tolerability a Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University Innsbruck, Innsbruck, Austria, b Otsuka Pharmaceutical Development Commercialization Inc., Princeton, New Jersey, c Otsuka Pharmaceutical Development Commercialization Inc., Rockville, Maryland and d The Zucker Hillside Hospital and the Hofstra North Shore-LIJ School of Medicine, Hempstead, New York, USA Correspondence to W. Wolfgang Fleischhacker, MD, Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria Tel: + 43 512 504 23669; fax: + 43 512 504 25267; e-mail: wolfgang.fleischhacker@i-med.ac.at Received 19 October 2012 Accepted 11 March 2013 Introduction Nonadherence to medication is one of the biggest challenges for patients receiving treatment for schizo- phrenia, and adherence problems are among the most frequent causes of relapse and rehospitalization (Kane, 2011). In this context, long-acting injectable (LAI) formulations of antipsychotics are a valuable treatment alternative, because they offer the possibility of helping patients remain adherent to their medication through regular contact with healthcare professionals and the prevention of covert nonadherence (Leucht et al., 2011). Despite the potential benefit of long-acting antipsycho- tics over their oral counterparts, questions about safety, tolerability, and initial dosing remain (Leucht et al., 2011). Safety and dosing issues are of particular importance because the adverse events (AEs) that emerge with LAI formulations cannot be addressed by immediately redu- cing the dose or stopping the medication, but must be actively managed. In addition, to make informed risk– benefit assessments possible and to manage AEs effec- tively, the safety profile during the switching period from oral to long-acting antipsychotics and during the initial period of the LAI antipsychotic needs to be fully understood. The long-term efficacy and safety profile of oral aripiprazole suggest that a LAI formulation may have a different risk– benefit profile than currently available long-acting atypical antipsychotics (Croxtall, 2012). Treatment with oral aripiprazole has shown a low potential for metabolic disturbances and sedation (Marder et al., 2003). Aripiprazole also has low potential for prolonged heart rate-corrected QT interval (QT c ) (Pigott et al., 2003; Fleischhacker et al., 2009). Although treatment with oral aripiprazole has been associated with akathisia, studies in patients with schizo- phrenia show that it occurs early in treatment, is mild to moderate in severity, and leads to few study discontinua- tions (Kane et al., 2010). Here, we report the time course of AEs after long-term exposure (over 52 weeks) to aripiprazole beginning with Clinical trial registration: Intramuscular Depot Formulation of Aripiprazole as Maintenance Treatment in Patients With Schizophrenia (ASPIRE). ID number: NCT00705783. Registry: clinicaltrials.gov. Original article 171 0268-1315  c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YIC.0b013e3283615dba Copyright © Lippincott Williams & Wilkins. 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